Field of the Invention
The present invention is directed to methods of treating and/or preventing
Social Communication Disorder in patients suffering from same. More particularly, the present disclosure is directed to a method of treating and/or preventing Social Communication Disorder by administration of insulin to the upper third of the patient's nasal cavity.
Description of the Related Art
Social Communication Disorder (SCD) may be described as a classification for characterizing children and others who have a primary difficulty with the pragmatic aspects of social communication (both comprehension and formulation) and with discourse comprehension, particularly affecting idiomatic and nonliteral language inferences in narrative texts and conversation. Social Communication Disorder (SCD) may be described as a classification for characterizing children and others who have a primary difficulty with the pragmatic aspects of social communication (both comprehension and formulation) and with discourse comprehension, particularly affecting idiomatic and nonliteral language inferences in narrative texts and conversation. The American Psychiatric Association (APA) has added SCD as a new category to the 5th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-5) allowing for a diagnosis of disability in social communication without the presence of repetitive behavior. The APA states that in order to diagnose SCD, first autistic spectrum disorders must be ruled out. Autistic spectrum disorders (ASD) by definition encompass pragmatic communication problems, but also include restricted, repetitive patterns of behavior, interests or activities as part of the autism spectrum. Therefore, autistic spectrum disorders need to be ruled out in order for SCD to be diagnosed. Consequently, SCD is a separate and wholly distinct disorder or condition from Autism and ASD. SCD can occur as a primary impairment or it can co-exist with other disorders. These diagnostic criteria for SCD were approved by the American Psychiatric Association (APA) Board of Trustees in Dec. 2012, and published in DSM-5 in 2013.
A person with SCD may exhibit persistent difficulties in pragmatics or the social uses of verbal and nonverbal communication in naturalistic contexts, which affects the development of social reciprocity and social relationships that cannot be explained by low abilities in the domains of word structure and grammar or general cognitive ability. Further, a person with SCD may have persistent difficulties in the acquisition and use of spoken language, written language, and other modalities of language (e.g. sign language) for narrative, expository and conversational discourse. Symptoms may affect comprehension, production, and awareness at a discourse level individually or in any combination that are likely to endure into adolescence and adulthood, although the symptoms, domains, and modalities involved may shift with age.
Symptoms of SCD must generally be present in childhood to be diagnosed as SCD, although symptoms may not become fully manifest until speech, language, or communication demands exceed limited capacities. For patients suffering from SCD, their low social communication abilities result in functional limitations in effective communication, social participation, academic achievement, or occupational performance, alone or in combination.
Signs typically appear in the first two years of a child's life. Early behavioral or cognitive intervention can help children gain self-care, social, and communication skills. There is presently no known cure. There is no consensus in the medical/research community as to what causes SCD or how to best treat it or prevent it.
SCD symptoms seem to result from changes in various systems of the brain, but how or why SCD occurs is not well understood. It is believed that SCD affects the amygdala, cerebellum, and many other parts of the brain.
In addition to various forms of therapy, many medications are used to treat SCD symptoms in conjunction with behavioral treatment or when behavioral treatment fails. Many patients diagnosed with SCD may be prescribed psychoactive drugs or anticonvulsants, including antidepressants, stimulants, and antipsychotics. A person with SCD may respond atypically to medications, the medications can have adverse effects, and no known medication relieves SCD's core symptoms of social and communication impairments.
A considerable amount of the old and new published work indicates that insulin signaling contributes to autism and may also contribute to SCD, and which indicates that using insulin to treat autism would either have no effect, or could even potentially exacerbate the symptoms. It has been theorized that insulin is capable of activating the precise cellular pathway implicated in autism, specifically that hyperactivation of the P13K/Tor pathway causes autism. The theory states that the P13K/Tor pathway is the major intracellular effector of insulin signals, and insulin signaling is predicted to activate the intracellular effector of insulin signals, and insulin signaling is predicted to activate the P13K/Tor pathway. As such, it has been theorized that insulin is capable of activating the precise cellular pathway implicated in autism.
Further support for this theory was found in another study in which the global cerebral metabolic rate (CMRglc) was 12% higher in autism patients than in controls. Further, FDG PET studies show increased glucose uptake and utilization in the frontal cortex in patients with autism, consistent with excessive insulin signaling.
Administration or application of at least an effective amount, or therapeutic dose, of certain therapeutic agent(s) and/or pharmaceutical compositions to the upper one-third of a mammalian patient's nasal cavity is a means to bypass the patient's blood-brain barrier (BBB) and actually deliver the effective amount, or therapeutic dose, of the administered/applied agent(s) and/or composition(s) directly to the patient's central nervous system.
Delivery of the agent and/or composition to the upper one third of the patient's nasal cavity is a means of bypassing the BBB to administer therapeutic compounds and/or agents directly to the CNS. Evidence exists that intranasal treatment with certain therapeutic agent(s) improves, i.e., prevents and/or treats, a variety of neurological and psychiatric disorders, e.g., stroke, in animals. This basic methodology is discussed and described in U.S. Pat. No. 5,624,898 to Frey II entitled Method for Administering Neurologic Agents to the Brain, as well as in U.S. Pat. No. 6,313,093 to Frey II, the entire contents of each of which are hereby incorporated by reference. This administration technique is a vast improvement over systemic administration methods such as intravenous and oral administration of drugs which generally cannot cross the BBB to reach their targets within the CNS. In addition, Frey's intranasal method is a significant improvement over the general inhalation methods which target the lower two-thirds of the patient's nasal cavity. Both the systemic and general intranasal method targeting the lower two-thirds of the nasal cavity result in a very large, unwanted and potentially dangerous systemic exposure to the administered drug or therapeutic agent(s). The present invention addresses, inter alia, this general intranasal problem as well as ensures that the patient's non-CNS, systemic disease and/or condition is protected from exposure to the therapeutic agent administered to the upper third of the nasal cavity, and potential harm therefrom.
General inhalation methods to the lower two-thirds of the nasal cavity delivered by, e.g., nasal spray bottles, on the other hand, result in a large amount of systemic absorption and exposure, with a very small amount of the administered compound, i.e., less than 5%, making the tortuous journey around the turbinates to the upper third of the nasal cavity and still less compound than that very small amount further bypassing the BBB to actually reach the CNS.
Delivery and administration to the upper third of the nasal cavity, is very effective in administering the subject compounds or agents to the desired target, i.e., the CNS, without significant systemic exposure, though some systemic exposure does occur as is further discussed below.
Unwanted systemic exposure of therapeutics used to treat CNS diseases create several serious problems. The systemic metabolism greatly reduces the bioavailability of any agent and/or compound exposed to the non-CNS system. This reduction of bioavailability is increased by unwanted plasma protein binding of the agent and/or compound. As a result, only a small amount of the active therapeutic agent and/or compound actually reaches the CNS. Because of these, inter alia, issues, the actual dose that must be administered in order to achieve a therapeutic dose in the targeted CNS is far larger than the therapeutic dosing. As a consequence, a relatively large concentration of the agent(s) and/or compounds(s) is in the system and will affect non-target systemic organs and systems. This can create unwanted and often dangerous side effects on these non-target organs and systems, particularly in the specific case of patient's having a systemic, non-CNS disorder or condition that contraindicates the systemic use or exposure of the therapeutic agent(s) needed to treat a CNS-related disorder or condition.
We have addressed the efficiency needs in patent application Ser. No. 12/134,385 to Frey II, et al., entitled “Pharmaceutical Compositions and Methods for Enhancing Targeting of Therapeutic Compounds to the Central Nervous System, the entire contents of which are hereby incorporated by reference, and wherein a vasoconstrictor is administered to the patient's nasal cavity either just prior to, or in combination with, administration of at least one therapeutic agent and/or pharmaceutical composition(s) comprising a therapeutic compound(s) and/or agent(s). The efficiency of the direct administration of the pharmaceutical compound to the CNS, with concomitant reduction of systemic exposure of the pharmaceutical compound is remarkable.
Moreover, we provide disclosure of the following patents and applications, each of which are commonly assigned with the present application and incorporated herein in their entirety for disclosure of, inter alia, the various diseases, conditions or disorders of the CNS relating herein to the first disease or condition of the present invention, as well as various compounds and/or therapeutic agents for treating same by application to the upper ⅓ of the nasal cavity, bypassing of the blood-brain barrier and subsequent direct delivery of the compounds and/or agents to the CNS:
U.S. Pat. No. 7,972,595 Methods and compositions for protecting and treating at least one muscarinic receptor from dysfunction not resulting from oxidative stress, toxic actions of metals or infectious agents by administering a pyrophosphate analog;
U.S. Pat. No. 7,786,166 Methods and compositions for protecting and treating muscarinic receptors through administration of at least one protective agent;
U.S. Pat. No. 7,776,312 Method of treating Alzheimer's disease comprising administering deferoxamine (DFO) to the upper one-third of the nasal cavity;
U.S. Pat. No. 7,618,615 Methods for providing neuroprotection for the animal central nervous system against neurodegeneration caused by ischemia;
U.S. Pat. No. 7,084,126 Methods and compositions for enhancing cellular function through protection of tissue components;
U.S. Pat. No. 6,313,093 Method for Administering Insulin to the Brain;
U.S. Pat Application 20100061959 Methods for Providing Neuroprotecton for the Animal Central Nervous System Against the Effects of Ischemia, Neurodegeneration, Trauma, and Metal Poisoning;
U.S. Patent Application 20080305077 Pharmaceutical Compositions and Method for Enhancing Targeting of Therapeutic Compounds to the Central Nervous System;
U.S. Patent Application 20110311654 Methods and Pharmaceutical Compositions for Treating the Animal Central Nervous System for Psychiatric Disorders;
U.S. Patent Application 20110236365 Method for Protecting and Treating at Least One Muscarinic Receptor From Dysfunction Resulting From Free Radical Damage.
While the use of insulin to treat autism, and possibly SCD has been generally taught against, even the therapeutic agents or compounds that are being used to treat central nervous system (CNS)-related conditions or diseases or disorders such as SCD may cause unnecessary, unwanted and potentially adverse side effects when given systemically or by general inhalation methods to the lower two-thirds of the patient's nasal cavity. In part, this may occur because systemic uptake dictates that a much larger dose be given, e.g., orally or intravenously, in order to ensure that an effective dose actually crosses the blood-brain barrier and enters the CNS. For example, gastric problems including GI upset, negative effects on blood pressure, and/or cardiac, liver, or kidney toxicity may result from systemic administration. Accordingly, a need exists for a therapeutic agent or compound that may be used to treat SCD. Further, a need exists for such a therapeutic agent or compound that minimizes the adverse side effects generally associated with administration of drugs used to treat CNS-related disorders. Still further, a need exists for a delivery system for such a composition that provides for enhanced uptake of the composition to maximize the therapeutic affect obtained per administration.
The present invention provides solutions for, inter alia, these problems.